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Gastric Acid Drugs

Gastric acid Gastric acid Hydrochloric acid present in gastric juice. Gastroesophageal Reflux Disease (GERD) medications include proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors (PPIs) and H₂ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonists (also known as H₂ blockers). The drugs work through different mechanisms to suppress acid secretion Secretion Coagulation Studies by parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy. The most common indications include peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease disease, GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD), and dyspepsia Dyspepsia Impaired digestion, especially after eating. Lactose Intolerance. Adverse effects of PPIs include malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion, acute interstitial nephritis Acute interstitial nephritis Inflammation of the interstitial tissue of the kidney. This term is generally used for primary inflammation of kidney tubules and/or surrounding interstitium. For primary inflammation of glomerular interstitium, see glomerulonephritis. Infiltration of the inflammatory cells into the interstitial compartment results in edema, increased spaces between the tubules, and tubular renal dysfunction. Acute Kidney Injury, and an increased risk of Clostridioides difficile infection. Adverse effects of H₂ blockers include CNS effects, bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias/ hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, and galactorrhea Galactorrhea Excessive or inappropriate lactation in females or males, and not necessarily related to pregnancy. Galactorrhea can occur either unilaterally or bilaterally, and be profuse or sparse. Its most common cause is hyperprolactinemia. Hyperprolactinemia. Both classes are associated with drug interactions related to the cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury system.

Last updated: Mar 15, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Physiology of acid secretion Secretion Coagulation Studies

Parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells are located in the body of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy and secrete hydrochloric acid Hydrochloric acid A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. Caustic Ingestion (Cleaning Products) ( HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia) into the lumen.

  • Water and CO₂ are combined to produce hydrogen (H+) ions and HCO₃ ions by the action of the carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors enzyme.
  • H+ is transported to the lumen of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy via the H+/K+ ATPase pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols.
  • HCO₃ is exchanged for chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes (Cl) ion.
  • H+ and Cl combine to form the final product Product A molecule created by the enzymatic reaction. Basics of Enzymes: HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
Ion transport in parietal cells

Ion transport in parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells:
Carbonic acid disassociates into a hydrogen (H+) ion and bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes (HCO3). The H+ is exchanged for potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia (K+) in the apical membrane by the H+/K+ ATPase. Bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes is exchanged for chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes (Cl) in the basolateral membrane, which then moves into the lumen. The Na+/K+ ATPase pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols in the basolateral membrane creates the cell’s electrochemical gradient Electrochemical gradient The Cell: Cell Membrane.

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Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and regulation

Acid production is stimulated by:

  • Acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS → muscarinic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Histamine release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology by enterochromaffin-like (ECL) cells → H₂ receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Gastrin Gastrin A family of gastrointestinal peptide hormones that excite the secretion of gastric juice. They may also occur in the central nervous system where they are presumed to be neurotransmitters. Gastrointestinal Secretions release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology by gastrin Gastrin A family of gastrointestinal peptide hormones that excite the secretion of gastric juice. They may also occur in the central nervous system where they are presumed to be neurotransmitters. Gastrointestinal Secretions cells → cholecystokinin-2/cholecystokinin-B receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Drug classes

Common medication classes used to control gastric acid Gastric acid Hydrochloric acid present in gastric juice. Gastroesophageal Reflux Disease (GERD) secretion Secretion Coagulation Studies include:

PPIs

Definition

Proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors are a group of drugs irreversibly inhibiting the H+/K+ ATPase pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols in gastric parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells.

Chemistry

  • Composed of 2 moieties: 
    • Benzimidazole
    • Pyridine
  • Weak bases Weak bases Acid-Base Balance
  • Includes:
    • Omeprazole
    • Lansoprazole
    • Pantoprazole
    • Rabeprazole

Mechanism of action

  • Administered as a prodrug Prodrug Nitroimidazoles → concentrated in secretory canaliculi of the parietal cell Parietal cell Rounded or pyramidal cells of the gastric glands. They secrete hydrochloric acid and produce gastric intrinsic factor, a glycoprotein that binds vitamin B12. Gastroesophageal Reflux Disease (GERD)
  • Converted to an active form (a sulfonamide Sulfonamide The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim cation) → covalently binds to the H+/K+ ATPase pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols
  • Causes irreversible inhibition → prevents movement of H+ into the gastric lumen → ↓ acid secretion Secretion Coagulation Studies
  • Inhibits both basal acid output and meal-stimulated output
Acid secretion

Mechanism of action of proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors (PPIs):
The drugs accumulate in the gland lumen, convert to the active form, and covalently bond to the H+/K+ ATPase, which results in irreversible pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inactivation and reduced acid secretion Secretion Coagulation Studies.

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Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:

  • The most common route of administration is oral, but the medications can also be given intravenously.
  • Inactive prodrugs
  • Acid labile Acid labile Vibrio → formulated as acid-resistant, enteric-coated tablets or capsules
  • Pass through the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy → absorbed in the alkaline intestinal lumen
  • Bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics is ↓ by the presence of food and should be administered 30–60 minutes prior to food intake.

Distribution:

  • Lipophilic 
  • Readily cross into acidified areas (e.g., the lumen of the parietal cell gland)
  • The serum half-life is short (called “hit-and-run” drugs because the duration of action is prolonged by approximately 24 hours).
  • 3–4 days for maximum effect

Metabolism: 

  • Rapid, hepatic 1st-pass metabolism
  • Cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
  • Dose reduction is required in severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease.

Excretion: 

  • Renal (primary)
  • Feces

Indications

  • Peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease disease ( PUD PUD Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease)
  • Stress ulcer prophylaxis Prophylaxis Cephalosporins
  • Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD) ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD))
  • Gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
  • Zollinger-Ellison syndrome Zollinger-ellison syndrome A syndrome that is characterized by the triad of severe peptic ulcer, hypersecretion of gastric acid, and gastrin-producing tumors of the pancreas or other tissue (gastrinoma). This syndrome may be sporadic or be associated with multiple endocrine neoplasia type 1. Esophagitis
  • Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori infection: component of triple and quadruple therapy
  • NSAID-induced ulcers

Adverse effects

  • General:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Abdominal pain Abdominal Pain Acute Abdomen
  • Nutritional side effects on prolonged therapy:
    • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion of vitamin B12
    • Calcium absorption Calcium absorption Digestion and Absorption → ↑ risk of fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures in elderly
    • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency
    • Hypomagnesemia Hypomagnesemia A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes
  • ↑ Risk of infection:
    • Clostridioides difficile
    • Bacterial gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
    • Community-acquired and nosocomial pneumonia Nosocomial pneumonia Pneumonia in Children
  • Gastrointestinal: 
    • Microscopic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis
    • Hypergastrinemia Hypergastrinemia Pancreatic Neuroendocrine Tumors (PanNETs)
    • Atrophic gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
    • Colonization Colonization Bacteriology of the intestine by multidrug resistant Multidrug resistant Resistant to at least 1 agent in > 3 antibiotic categories Pseudomonas organisms
  • Other:
    • Acute interstitial nephritis Acute interstitial nephritis Inflammation of the interstitial tissue of the kidney. This term is generally used for primary inflammation of kidney tubules and/or surrounding interstitium. For primary inflammation of glomerular interstitium, see glomerulonephritis. Infiltration of the inflammatory cells into the interstitial compartment results in edema, increased spaces between the tubules, and tubular renal dysfunction. Acute Kidney Injury
    • Drug-induced lupus Drug-Induced Lupus Systemic Lupus Erythematosus

Drug interactions

  • Interactions due to CYP450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
    • ↓ Activity:
      • Clopidogrel Clopidogrel A ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation. Antiplatelet Drugs requires CYP219 for action → concurrent use of PPI can ↓ anticoagulant and antiplatelet action
      • Theophylline Theophylline A methyl xanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities. Theophylline inhibits the 3. Asthma Drugs
      • HIV HIV Anti-HIV Drugs protease inhibitors Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). Anti-HIV Drugs
    • PPIs inhibit the metabolism of:
      • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
      • Diazepam Diazepam A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. Benzodiazepines
      • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs 
  • ↓ Gastric acidity can alter the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of medications:
    • Ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles
    • Amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants (e.g., dextroamphetamine Dextroamphetamine The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monoamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. Stimulants)

H₂ Receptor Antagonists

Definition

H₂ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonists (also known as H₂ blockers) are competitive inhibitors of H₂ receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells, which aid in the reduction of acid secretion Secretion Coagulation Studies.

Chemistry

  • Histamine-based molecules
  • Includes: 
    • Famotidine Famotidine A competitive histamine h2-receptor antagonist. Its main pharmacodynamic effect is the inhibition of gastric secretion. Antihistamines
    • Cimetidine Cimetidine A histamine congener, it competitively inhibits histamine binding to histamine h2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. Antihistamines
    • Nizatidine Nizatidine A histamine h2 receptor antagonist with low toxicity that inhibits gastric acid secretion. The drug is used for the treatment of duodenal ulcers. Antihistamines 
    • Ranitidine (withdrawn from the market in the United States in 2020)

Mechanism of action

  • Competitive, reversible antagonists of H2 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on gastric parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells:
    • Histamine is blocked from binding to the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → ↓ cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors → ↓ protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons activation 
    • ↓ Activation of H+/K+ ATPase → ↓ acid secretion Secretion Coagulation Studies
    • Additional consequence: ↓ effect of acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS and gastrin Gastrin A family of gastrointestinal peptide hormones that excite the secretion of gastric juice. They may also occur in the central nervous system where they are presumed to be neurotransmitters. Gastrointestinal Secretions on parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells
  • ↓ Basal output and meal-stimulated output
Mechanism of action for h2 receptor antagonists

Mechanism of action for H2 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonists (H2 blockers):
The antihistamine effect blocks the activation of H+/K+ ATPase through the cAMP-dependent pathway, resulting in decreased acid secretion Secretion Coagulation Studies.

Image by Lecturio.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Given in oral and IV preparations
    • Well absorbed
    • Not affected by food
  • Distribution:
    • Onset of action: 30–60 minutes
    • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics range: 1–4 hours
    • The volume of distribution decreases in the elderly.
    • Crosses the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity and is secreted in breast milk
  • Metabolism:
    • Hepatic 1st-pass metabolism
    • Some are metabolized by the cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury system.
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy: renal 

Indications

  • GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD)
  • Dyspepsia Dyspepsia Impaired digestion, especially after eating. Lactose Intolerance
  • PUD PUD Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease
  • Stress-ulcer prophylaxis Prophylaxis Cephalosporins
  • Prevention of aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Anaphylaxis Anaphylaxis An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. Type I Hypersensitivity Reaction (in combination therapy)

Adverse drug reactions

  • General: 
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • CNS effects (associated with IV administration): 
    • Confusion
    • Hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
    • Agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus
  • Cardiovascular (associated with rapid IV administration):
    • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Reproductive effects (cimetidine-related): 
    • Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia
    • Impotence in men
    • Galactorrhea Galactorrhea Excessive or inappropriate lactation in females or males, and not necessarily related to pregnancy. Galactorrhea can occur either unilaterally or bilaterally, and be profuse or sparse. Its most common cause is hyperprolactinemia. Hyperprolactinemia in women 
  • Other:
    • Vitamin B12 deficiency (with long-term use)
    • Myelosuppression Myelosuppression Oxazolidinones
    • Necrotizing enterocolitis Necrotizing enterocolitis Necrotizing enterocolitis (NEC) is an intestinal inflammatory process that can lead to mucosal injury and necrosis. The condition is multifactorial, with underlying risk factors that include prematurity and formula feeding. The clinical presentation varies in severity from feeding intolerance, acute findings on abdominal exam, and systemic symptoms. Necrotizing Enterocolitis in very low birth weight neonates

Drug interactions

The medications can be potent inhibitors of cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury (particularly cimetidine Cimetidine A histamine congener, it competitively inhibits histamine binding to histamine h2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. Antihistamines), resulting in ↑ plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentrations of:

  • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
  • Theophylline Theophylline A methyl xanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities. Theophylline inhibits the 3. Asthma Drugs
  • Carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs
  • Tacrolimus Tacrolimus A macrolide isolated from the culture broth of a strain of streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. Immunosuppressants
  • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • Many other drugs

References

  1. Katzung, Bertram G., and Trevor, Anthony J., editors. Basic & Clinical Pharmacology. 13. ed, McGraw-Hill Education, 2015.
  2. Hilal-Dandan, Randa, et al. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. 2014. Open WorldCat, http://accesspharmacy.mhmedical.com/book.aspx?bookid=1810
  3. Le, Tao, et al. First Aid for the USMLE Step 1 2020. 2020. Open WorldCat, https://mhebooklibrary.com/doi/book/10.1036/9781260462050
  4. Vakil N.B. (2020). Peptic ulcer disease: Treatment and secondary prevention. Retrieved 27 November 2020, from https://www.uptodate.com/contents/peptic-ulcer-disease-treatment-and-secondary-prevention
  5. Vakil N.B. (2020). Peptic ulcer disease: Epidemiology, etiology, and pathogenesis. Retrieved 27 November 2020, from https://www.uptodate.com/contents/peptic-ulcer-disease-epidemiology-etiology-and-pathogenesis
  6. Wolfe, M.M. (2020). Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid-related disorders. In Grover, S. (Ed.), UpToDate. Retrieved July 16, 2021, from https://www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders
  7. Vakil, N.B. (2020). Antiulcer medications: Mechanism of action, pharmacology, and side effects. In Grover, S. (Ed.), UpToDate. Retrieved July 16, 2021, from https://www.uptodate.com/contents/antiulcer-medications-mechanism-of-action-pharmacology-and-side-effects
  8. Costanzo L. (2018). Physiology. Philadelphia: Mosby Elsevier
  9. “List of Proton Pump Inhibitors + Uses, Side Effects.” Drugs.com, https://www.drugs.com/drug-class/proton-pump-inhibitors.html
  10. Vakil, N. (2021). Drug treatment of gastric acidity. [online] MSD Manual Professional Version. Retrieved July 16, 2021, from https://www.msdmanuals.com/professional/gastrointestinal-disorders/gastritis-and-peptic-ulcer-disease/drug-treatment-of-gastric-acidity

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